Insights into phenotypic variability caused by GARS1 pathogenic variants

Abstract

Background and purpose: Pathogenic variants of the glycyl-tRNA synthetase 1 (GARS1) gene have been described as a cause of Charcot-Marie-Tooth disease type 2D, motor axonal neuropathy with upper limb predominance (distal hereditary motor neuropathy [dHMN] type V), and infantile spinal muscular atrophy.

Methods: This cross-sectional, retrospective, observational study was carried out on 12 patients harboring the c.794C>T (p.Ser265Phe) missense pathogenic variant in GARS1. The patients' clinical data, nerve conduction studies, magnetic resonance imaging (MRI), and intraepidermal nerve fiber density in skin biopsies were reviewed.

Results: The mean age at onset was 9.5 years; the intrinsic hand muscles were affected before or at the same time as the distal leg musculature. The clinical examination revealed greater weakness of the distal muscles, with a more pronounced involvement of the thenar complex and the first dorsal interosseous in upper limbs. Electrophysiological studies were concordant with an exclusively motor axonal neuropathy. A pathologic split hand index was found in six patients. Muscle MRI showed predominant fatty infiltration and atrophy of the anterolateral and superficial posterior compartment of the legs. Most patients reported distal pinprick sensory loss. A reduced intraepidermal nerve fiber density was evident in skin biopsies from proximal and distal sites in nine patients.

Conclusions: GARS1 variants may produce a dHMN phenotype with "split hand" and sensory disturbances, even when sensory nerve conduction studies are normal. This could be explained by a dysfunction of sensory neurons in the dorsal ganglion that is reflected as a reduction of dermal nerve endings in skin biopsies without a distal gradient.

Keywords: Charcot–Marie–Tooth disease; GARS1 gene; axonal CMT; skin biopsy; split hand.

FIGURE 1

Family 1 and 2 pedigrees. All cases are numbered as they are referenced in the article and tables. Squares represent men, and circles are women. Filled symbols signify affected individuals. The letters under each individual represent the available information: clinical (C), neurophysiological (E: electroneurography, SEP: sensory evoked potentials), radiological (RM: magnetic resonance imaging), and anatomopathological (SB: skin biopsy) evaluation. ? indicates uncertain state. *Affected by clinical history but not included in this study, as they could not be evaluated.

FIGURE 2

Images of the hands of Patient F1/IV:8. Atrophy is seen of the thenar eminence and the first dorsal interosseous, preserving the muscle mass in the hypothenar eminence (split hand). The patient had clear difficulty abducting the second finger.

FIGURE 3

Distal lower limb skin biopsies and magnetic resonance imaging (MRI) from patients F2/IV:9 (left column) and F1/IV:17 (right column). In both skin biopsies (a, e), the intraepidermal fiber count (red arrows) was lower than normative values. (b–d) Patient F2/IV:9 MRI T1‐weighted (T1w) images of the legs and feet showing a relative sparing of the proximal regions of the legs (b), a moderate atrophy and fatty infiltration in the distal portions of anterolateral and superficial posterior compartments (c, red arrows) and a focal infiltration of the lateral compartment of the right foot (d, red arrow) with mild atrophy of the interosseous muscles (partially shown in the image). (f–h) Patient F1/IV:17 MRI T1w images of the legs and feet showing a marked atrophy and fatty infiltration of the anterolateral and superficial posterior compartment with a distal to proximal gradient of fat replacement (f, g), with a relative sparing of deep posterior compartment muscles (g, red arrow) and a severe atrophy and fatty replacement of foot muscles (h).